Recent evidence indicates that survival of naive peripheral T cells is an active process requiring the interaction of the T cell receptor with self-peptides presented by the same MHC molecules that are responsible for thymic selection. However this T cell receptor interaction with self MHC does not lead to T cell activation because this process is dampened by a family of negative regulators of activation. Recent work from our group indicates that faulty negative regulation may permit the activation of autoreactive T cells, and that intrinsic hyporesponsiveness of T cell receptor signaling in autoimmune prone animals may further enhance any deficiency in negative regulation. Together, these conditions can lead to enrichment of peripheral autoreactive T cells and ultimately instigate autoimmune disease. This application will reinforce a collaboration between two laboratories with expertise in cell cycle regulation and the immunbiology of Type I diabetes. The experiments proposed are designed to test the hypotheses that (1) failure of negative regulation leads to abortive cell cycle entry and death unless the T cells receive a strong survival signal and (2) because of an intrinsic hyporesponsiveness in T cell receptor signaling the failure of negative regulation preferentially permits the expansion of autoreactive clones resulting in autoimmunity.